Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

Investigation of the Structure Design and Heat Transfer Characteristics of Heating Cable

Indoor heating with an electrical heating cable,which has no harmful emissions to the environment,is an attractive way for radiant floor heating.To improve the heat transfer efficiency,a novel structure of the heating cable was designed by proposing the concept of the aluminum finned sheath.The transient heat transfer model from the embedded heating cables to the floor is established to validate the feasibility of this novel cable.The effects of the fin number and shape on the cable’s temperature and heat flux distribution were analyzed.The results show that,with the specific volume of the sheath,increasing the number of fins can enhance the thermal diffusion capacity of the heating cable and reduce its temperature.Rectangular fins exhibit higher performance for heat dissipation than triangular fins due to their larger surface area.The simulation result shows that the floor temperature above the cable rises from 5°C to 22.5°C after a 2-h heating process,which was validated with experimental results.The results and suggestions can provide reference to guide the design of the heating cable.

Evaluation of immunoprotection against coronavirus disease 2019:Novel variants,vaccine inoculation,and complications

The strikingly rapidly mutating nature of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)genome has been a constant challenge during the coronavirus disease 2019(COVID-19)pandemic.In this study,various techniques,including reverse transcription-quantitative polymerase chain reaction,antigen-detection rapid diagnostic tests,and high-throughput sequencing were analyzed under different scenarios and spectra for the etiological diagnosis of COVID-19 at the population scale.This study aimed to summarize the latest research progress and provide up-to-date understanding of the methodology used for the evaluation of the immunoprotection conditions against future variants of SARS-CoV-2.Our novel work reviewed the current methods for the evaluation of the immunoprotection status of a specific population(endogenous antibodies)before and after vaccine inoculation(administered with biopharmaceutical antibody products).The present knowledge of the immunoprotection status regarding the COVID-19 complications was also discussed.Knowledge on the immunoprotection status of specific populations can help guide the design of pharmaceutical antibody products,inform practice guidelines,and develop national regulations with respect to the timing of and need for extra rounds of vaccine boosters.

A new model for Doppler shift of C-band echoes backscattered from sea surface

Within the framework of the two-scale scattering model,the Doppler shift of C-band radar return signals from the nonlinear sea surface are numerically evaluated.As an analytical approximation method,the Bragg resonance scattering method cannot accurately describe the backscattering field from sea surface.Therefore,in the twoscale scattering model,more accurate scattering coefficient(the normalized radar cross section,NRCS)evaluated by the C-band dual-polarized(HH/VV)empirical geophysical model function(CSAR model)is employed to replace the traditional Bragg NRCS to weight the Doppler shift.The numerical results indicate that there are obvious differences between the Doppler shift weighted by the CSAR NRCS and that weighted by the traditional Bragg NRCS.The hydrodynamic modulation of the large-scale waves is one of the important factors that affect the difference between the Doppler shift predicted in upwind and downwind directions.If the relaxation rate in the hydrodynamic modulation is set to be the angular frequency of the dominant water waves,the Doppler shift predicted by the numerical method can fit the results of the empirical model(C-band empirical geophysical model function,CDOP)well at moderate wind speed.Under low wind condition,the comparison shows that the empirical CDOP model appears to overestimate the Doppler shift.In order to facilitate the application,at the end of this paper a semi-empirical CSAR-DOP model,which is a polynomial fitting formula,is developed for evaluating the Doppler shift of C-band signals from time varying sea surface.

The Physiological Basis of Heterosis for Potassium Uptake of Hybrid Millet

Hybrid millet Zhang and its parental cultivars were studied for their potassium (K) uptake and accumulation characteristics and related physiological mechanisms. Hydroponic culture was performed with two K levels (i.e., high and low) set up. At high K level, hybrid millet showed heterobeltiosis in K accumulation and leaf K content, and it also had higher H+-ATPase activity, respiration rate, root oxidant activity and root K+ influx rate than its parental cultivars. All these lay the physiological foundation of heterosis for potassium uptake of hybrid millet. At low K level, the hybrid millet had a lower H+-ATPase activity and a higher K efflux rate than its parental cultivars, thus heterobeltiosis in K accumulation or leaf K content was not observed. Therefore, high level K fertilizer application is recommended for hybrid millet cultivation as it is favorable for hybrid millet to display heterosis in K uptake and K accumulation.

The influences of environmental factors on the air-sea coupling coefficient

The response relationship between equivalent neutral wind speed anomaly(ENWSA)and sea-air temperature difference anomaly(SATDA)has been analyzed over four typical sea regions,i.e.,the Kuroshio Extension,the Gulf Stream,the Brazil-Malvinas Confluence and the Agulhas Return Current.The results show that ENWSA is more sensitive to SATDA than sea surface temperature anomaly(SSTA),which implies that SATDA seems to be a more suitable parameter than SSTA to analyze the mesoscale air-sea interactions.Here,the slope of the linear relation between ENWSA and SATDA is defined as the air-sea coupling coefficient.It is found that the values of the coupling coefficient over the four typical sea areas have obvious seasonal variations and geographical differences.In order to reveal the reason of the seasonal variation and geographical difference of the coupling coefficient,the influences of some environmental background factors,such as the spatially averaged sea surface temperature(SST),the spatially averaged air temperature,the spatially averaged sea-air temperature difference and the spatially averaged equivalent neutral wind speed,on the coupling coefficient are discussed in detail.The results reveal that the background sea-air temperature difference is an important environmental factor which directly affects the magnitude of the coupling coefficients,meanwhile,the seasonal and geographical variations of the coupling coefficient.

Intelligent nanoreactor coupling tumor microenvironment manipulation and H_(2)O_(2)-dependent photothermal-chemodynamic therapy for accurate treatment of primary and metastatic tumors

Tumor microenvironment(TME),as the“soil”of tumor growth and metastasis,exhibits significant differences from normal physiological conditions.However,how to manipulate the distinctions to achieve the accurate therapy of primary and metastatic tumors is still a challenge.Herein,an innovative nanoreactor(AH@MBTF)is developed to utilize the apparent differences(copper concentration and H_(2)O_(2)level)between tumor cells and normal cells to eliminate primary tumor based on H_(2)O_(2)-dependent photothermal-chemodynamic therapy and suppress metastatic tumor through copper complexation.This nanoreactor is constructed using functionalized MSN incorporating benzoyl thiourea(BTU),triphenylphosphine(TPP),and folic acid(FA),while being co-loaded with horseradish peroxidase(HRP)and its substrate ABTS.During therapy,the BTU moieties on AH@MBTF could capture excessive copper(highly correlated with tumor metastasis),presenting exceptional anti-metastasis activity.Simultaneously,the complexation between BTU and copper triggers the formation of cuprous ions,which further react with H_(2)O_(2)to generate cytotoxic hydroxyl radical(•OH),inhibiting tumor growth via che-modynamic therapy.Additionally,the stepwise targeting of FA and TPP guides AH@MBTF to accurately accu-mulate in tumor mitochondria,containing abnormally high levels of H_(2)O_(2).As a catalyst,HRP mediates the oxidation reaction between ABTS and H_(2)O_(2)to yield activated ABTS•^(+).Upon 808 nm laser irradiation,the activated ABTS•^(+)performs tumor-specific photothermal therapy,achieving the ablation of primary tumor by raising the tissue temperature.Collectively,this intelligent nanoreactor possesses profound potential in inhib-iting tumor progression and metastasis.

通过氮含量调控ZrN薄膜中的超导圆顶

超导圆顶作为非常规超导材料的一个常见特征,其存在经常被用来作为区分常规与非常规超导材料的判别标准.本文利用脉冲激光沉积氮化锆薄膜,并通过改变薄膜中的氮含量,实现了超导圆顶于绝缘态附近的调控。利用电学输运、磁性表征、太赫兹光谱、拉曼散射和透射电镜综合实验手段与密度泛函计算,作者发现氮化锆薄膜正常态存在从强绝缘到金属态再到弱绝缘的转变,其电阻率表现出类似于非常规超导的线性温度依赖到二次温度依赖特征.而氮化锆超导能隙及其转变温度符合BCS预期,其超导圆顶的演化与材料中电声耦合强度及结构无序相关,这项工作为“常规”超导材料中存在的“非常规”超导圆顶提供了强有力的证据与实例.

A dual-responsive hyaluronic acid nanocomposite hydrogel drug delivery system for overcoming multiple drug resistance

Chemotherapy is restricted by efficient drug outflow due to the multiple drug resistance(MDR)in heterogenous nature of tumor.Herein,we present a dual-responsive hyaluronic acid(HA)nanocomposite hydrogel that can not only response to the tumor microenvironment but also enhance chemotherapy.This HA hydrogel consists of a core-shell SiO_(2)(GOD@SiO_(2)-Arg)and mesoporous silica nanoparticles(MSNs)with doxorubicin(DOX)as the cargo(DOX@MSN).It could rapidly release the GOD@SiO_(2)-Arg nanoparticles at the low p H tumor-specific environment due to the cleavage of imine bond.GOD@SiO_(2)-Arg activated by over-expressed glutathione(GSH)in tumor cells releases GOD due to the cleavage of disulfide bonds,which could oxidize glucose to produce hydrogen peroxide(H2O2)for in situ NO generation via reaction between Arg and H2O2.The validity of this study might provide a method to modulate the tumor microenvironment for enhancing chemotherapy.

9,10-Bis(diphenylmethylene)-9,10-dihydroanthracene-based metal-organic assemblies with aggregation-induced emission for multiple sensing

Developing novel emissive supramolecular assemblies with elegant architectures and tunable perfor-mance remains highly desirable yet challenging.Herein,we report the design and synthesis of several 9.10-bis(diphenylmethylene)-9.10-dihydroanthracene-based metal organic assembles with aggregation-induced emission characteristics.Such assemblies feature intriguing thermochromic and mechanochromic properties,ie.,distinguishable fuorescence responses in terms of emission wavelength and intensity un-der variable temperatures and pressures.Moreover,these assemblies can serve as excellent fluorescent sensors for the detection of polysaccharide molecules.Due to the differentiated charge type and den-sity,the assembles display distinct sensing mechanisms toward different polysaccharide molecules.This study provides novel perspectives for the synthesis of buttrfly-like platinum(I)supramolecular coordi-nation complexes with multistimuli-responsiveness for polysaccharide sensing.which will facllitate the development of stimuli-responsive materials.

Cationic telluroviologen derivatives as type-I photosensitizers for tumor photodynamic theranostics

The hypoxia of the tumor microenvironment(TME)seriously restricts the photodynamic therapy(PDT)effect of conventional type-II photosensitizers,which are highly dependent on O_(2).In this work,a new type-I photosensitizer(TPE-TeVPPh3)consisting of a tetraphenylethylene group(TPE)as a bioimaging moiety,triphenyl-phosphine(PPh3)as a mitochondria-targeting group,and telluroviologen(TeV2+)as a reactive oxygen species(O_(2)•−,•OH)generating moiety is developed.The luminescence intensity of TPE-TeV-PPh3 increased significantly after specific oxidation by excess H2O2 in the TME without responding to normal tissues via the formation of Te═O bond,which can be used for monitoring abnormal H2O2,positioning,and imaging of tumors.TPE-TeV-PPh3 with highly reactive radicals generation and stronger hypoxia tolerance realizes efficient cancer cell killing under hypoxic conditions,achieving 88%tumor growth inhibition.Therefore,TPE-TeV-PPh3 with low phototoxicity in normal tissue achieves tumor imaging and effective PDT toward solid tumors in response to high concentrations of H_(2)O_(2)in the TME,which provides a new strategy for the development of type-I photosensitizers.

乳酸及降钙素原对一氧化碳中毒后迟发性脑病的预测价值

目的探讨检测血乳酸、降钙素原和联合检测对急性一氧化碳中毒后迟发性脑病(DEACMP)的预测价值。方法随机抽取我院在急诊科收住院的ACMP患者70例,随访3个月,以其中发生DEACMP患者10例为DEACMP组,其余60例为非DEACMP组,随机抽取同期笔者医院40例健康体检者为对照组。对患者立即行动脉血Lac和血清PCT检测,并计算Lac和PCT诊断DEACMP的灵敏度、特异度。结果DEACMP组血Lac和PCT检测值均明显高于非DEACMP和对照组,差异有统计学意义(采用秩和检验,P<0.05);检测异常率亦明显高于非DEACMP组及对照组,差异有统计学意义(采用χ2检验,P<0.05)。Lac和PCT升高预测DEACMP的敏感度均为90.0%,特异度分别为50.0%和65.0%,准确性分别为55.7%和68.6%。联合检测时若其中1个指标为阳性时即预测DEACMP发病,则联合检测的敏感度为100.0%,特异度为41.7%,阳性预测值为21.7%,阴性预测值为100.0%,准确性为71.4%。结论DEACMP患者早期动脉血Lac和PCT均明显升高,PCT诊断价值优于Lac,联合检测较单项指标检测对DEACMP发病预测价值更理想。

新早期胃癌标志物PRDX4通过清除ROS促进胃癌的发生发展（英文）

胃癌是全球第四大最常见的癌症,也是全球癌症中引起死亡的第二大原因。为了降低胃癌的死亡率,目前亟需解决的问题是发现新的早期胃癌特异性的标志物,提高早期胃癌的检出率,从而从根本上解决胃癌死亡率高的问题。实验室前期研究发现过氧化物酶4 (Peroxiredoxin 4,PRDX4)具有早期胃癌标志物的潜能,文中通过建立恶性转化模型及转化细胞过表达等方法,研究PRDX4在转化细胞中的作用。结果显示PRDX4通过减少转化细胞中活性氧(Reactive oxygen species,ROS)含量,使细胞处在利于生长增殖的微环境中,从而促进细胞发生恶性转化,即PRDX4通过清除ROS促进胃癌的发生发展。

2018 Chinese Pediatric Cardiology Society(CPCS) guideline for diagnosis and treatment of syncope in children and adolescents

Syncope belongs to the transient loss of consciousness(TLOC), characterized by a rapid onset, short duration, and spontaneous complete recovery. It is common in children and adolescents, accounting for 1% to 2% of emergency department visits.Recurrent syncope can seriously affect children's physical and mental health, learning ability and quality of life and sometimes cardiac syncope even poses a risk of sudden death. The present guideline for the diagnosis and treatment of syncope in children and adolescents was developed for guiding a better clinical management of pediatric syncope. Based on the globally recent development and the evidence-based data in China, 2018 Chinese Pediatric Cardiology Society(CPCS) guideline for diagnosis and treatment of syncope in children and adolescents was jointly prepared by the Pediatric Cardiology Society, Chinese Pediatric Society, Chinese Medical Association(CMA)/Committee on Pediatric Syncope, Pediatricians Branch, Chinese Medical Doctor Association(CMDA)/Committee on Pediatric Cardiology, Chinese College of Cardiovascular Physicians, Chinese Medical Doctor Association(CMDA)/Pediatric Cardiology Society, Beijing Pediatric Society, Beijing Medical Association(BMA). The present guideline includes the underlying diseases of syncope in children and adolescents, the diagnostic procedures, methodology and clinical significance of standing test and headup tilt test, the clinical diagnosis vasovagal syncope, postural orthostatic tachycardia syndrome, orthostatic hypotension and orthostatic hypertension, and the treatment of syncope as well as follow-up.

Application of regional citrate anticoagulation in patients at high risk of bleeding during intermittent hemodialysis:a prospective multicenter randomized controlled trial

Objective:Safe and effective anticoagulation is essential for hemodialysis patients who are at high risk of bleeding.The purpose of this trial is to evaluate the effectiveness and safety of two-stage regional citrate anticoagulation(RCA)combined with sequential anticoagulation and standard calcium-containing dialysate in intermittent hemodialysis(IHD)treatment.Methods:Patients at high risk of bleeding who underwent IHD from September 2019 to May 2021 were prospectively enrolled in 13 blood purification centers of nephrology departments,and were randomly divided into RCA group and saline flushing group.In the RCA group,0.04 g/mL sodium citrate was infused from the start of the dialysis line during blood draining and at the venous expansion chamber.The sodium citrate was stopped after 3 h of dialysis,which was changed to sequential dialysis without anticoagulant.The hazard ratios for coagulation were according to baseline.Results:A total of 159 patients and 208 sessions were enrolled,including RCA group(80 patients,110 sessions)and saline flushing group(79 patients,98 sessions).The incidence of severe coagulation events of extracorporeal circulation in the RCA group was significantly lower than that in the saline flushing group(3.64%vs.20.41%,P<0.001).The survival time of the filter pipeline in the RCA group was significantly longer than that in the saline flushing group((238.34±9.33)min vs.(221.73±34.10)min,P<0.001).The urea clearance index(Kt/V)in the RCA group was similar to that in the saline flushing group with no statistically significant difference(1.12±0.34 vs.1.08±0.34,P=0.41).Conclusions:Compared with saline flushing,the two-stage RCA combined with a sequential anticoagulation strategy significantly reduced extracorporeal circulation clotting events and prolonged the dialysis time without serious adverse events.

EGFR/cell membrane chromatography-online-high performance liquid chromatography/mass spectrometry method for screening EGFR antagonists from Radix Angelicae Pubescentis

The intracellular kinase domains of the epidermal growth factor receptor(EGFR) in some tumor cells are significant targets for drug discovery.We have developed a new EGFR cell membrane chromatography(EGFR/CMC)-online-high performance liquid chromatography/mass spectrometry(HPLC/MS) method for screening anti-EGFR antagonists from medicinal herbs such as Radix Angelicae Pubescentis.In this study,the HEK293 EGFR cells with high expression of EGFR were used to prepare cell membrane stationary phase(CMSP) in the EGFR/CMC model.The retention fractions on the EGFR/CMC model were directly analyzed by combining a 10 port columns switcher with a HPLC/MS system online.As a result,osthole from Radix Angelicae Pubescentis was found to be the active component acting on EGFR like dasatinib as the control drug.There was a good relationship between their inhibiting effects on EGFR secretion and HEK293 EGFR cell growth in vitro.This new EGFR/CMC-online-HPLC/MS method can be applied for screening anti-EGFR antagonists from TCMs,for instance,Radix Angelicae Pubescentis.It will be a useful method for drug discovery with natural medicinal herbs as a leading compound resource.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Cyanostilbene-based near-infrared emissive platinum(Ⅱ) metallacycles for cancer theranostics

In this work,a near-infrared emissive dipyridyl ligand was synthesized and used to prepare three platinum(II)metallacycles with different shapes via metal-coordination-driven self-assembly with different platinum(II)precursors.These metallacycles were further used for both cell imaging and cancer therapy,offering a new type of theranostic agents towards cancer treatment.

Cu-10Sn-4Ni-3Pb Alloy Prepared by Crystallization Under Pressure: An Experimental Study

The wear-resistant tin bronze （Cu-10Sn-4Ni-3Pb） with tin content above 8 wt.% prepared by traditional melting and casting process usually defects such as low density, poor properties and segregations. The crystallization under pressure processing of Cu-10Sn-4Ni-3Pb alloy was investigated. The microstructures were observed and analyzed and compared with that by traditional melting and casting process. The results show that the dendrite has obviously disappeared and the dendritic segregation alleviated by using the crystallization under 680 MPa pressure process, in comparison with the remarkably dendrite microstructure and severe as-cast defects of alloy prepared by traditional melting and casting technology. Based on the experimental study, the properties and microstructures of Cu-10Sn-4Ni-3Pb tin bronze prepared by crystallization under pressure have been improved significantly.